Predicting Δ-9-Tetrahydrocannabinol-Induced Psychoactive and Cognitive Effects: A PBPK-PD Approach to Quantifying Feeling High and Reduced Alertness

Abstract

The increasing use of cannabis for medicinal and recreational purposes highlights the need to understand its psychoactive effects. Δ-9-tetrahydrocannabinol (THC), the primary psychoactive cannabinoid, is responsible for feeling high and reduced alertness after cannabis use. This study aimed to develop and verify physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) models to quantify the effects of THC and its active metabolite, 11-hydroxy-THC, on feeling high and reduction in alertness in healthy adults. The models were developed using Simcyp, based on our previously verified THC PBPK model. A direct response model with a maximum effect (E_max) function driven by the brain concentrations and an effect compartment was used to describe visual analogue scale (VAS) scores for feeling high after intravenous, oral, and inhaled THC administration. An indirect response model with an E_max function driven by the brain concentrations was used to describe the reduction in VAS alertness scores after inhaled THC. Our models accurately captured the dose-response relationships for THC doses ranging from 2 to 86 mg for feeling high, and 2 to 69.4 mg for alertness reduction. The verified PBPK-PD model provides a robust tool for predicting the psychoactive and cognitive effects of THC, enabling improved assessment of cannabis-induced responses across diverse populations.

Keywords: PBPK−PD; alertness; feeling high; pharmacodynamics; psychoactive; Δ-9-tetrahydrocannabinol.

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Observed vs PBPK–PD model-predicted (A) peak VAS “feeling high” and (B) trough VAS “alertness” following THC administration to healthy adults by multiple routes of administration.

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Observed vs PBPK–PD model-predicted VAS “feeling high”. The blue shaded areas represent the 5th to 95th percentiles of predicted values. The blue lines and orange circles represent the mean predicted value and observed VAS “feeling high” scores, respectively. Noted data for Strougo 2008 and Klumpers 2012 are presented as Log₁₀(VAS + 2), as reported in the original studies.

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PBPK–PD model-predicted (A,B) VAS “feeling high” and (C,D) VAS “alertness” following (A,C) oral and (B,D) inhaled THC administration with a dose range from 1 mg to 100 mg at a rest condition. The gray shaded areas represent the 5th to 95th percentiles of predicted VAS scores. The black lines represent the mean predicted VAS scores. The orange dashed lines represent specific doses.

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Observed vs PBPK–PD model-predicted VAS “alertness”. The blue shaded areas represent the 5th to 95th percentiles of predicted values. The blue lines and orange circles represent the mean predicted value and observed VAS “alertness” scores, respectively.

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General workflow for Δ-9-tetrahydrocannabinol (THC) physiologically based pharmacokinetic–pharmacodynamic (PBPK–PD) model for visual analogue scale (VAS) “feeling high” and VAS “alertness”. PK, pharmacokinetic; IV, intravenous.